Method for treatment of moderate to severe erythema symptoms in rosacea patients

ABSTRACT

A regimen for the therapeutic treatment of moderate to severe erythema symptoms in rosacea patients, the regimen comprising topically applying to the skin of a subject in need of said treatment a pharmaceutical composition, the pharmaceutical composition comprising about 1% w/w to about 10% w/w benzoyl peroxide as an active ingredient, and a pharmaceutically acceptable carrier or excipient, wherein the benzoyl peroxide is the only active ingredient in said pharmaceutical composition, wherein said pharmaceutical composition is applied once daily for a period of at least about 12 weeks, to achieve a percentage decrease of about 60% in a population exhibiting moderate to severe erythema symptoms when measured at about 12 weeks after initial treatment of the population with the pharmaceutical composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) from U.S.Provisional Application No. 62/977,974, filed Feb. 18, 2020, U.S.Provisional Application No. 62/977,952, filed Feb. 18, 2020, U.S.Provisional Application No. 62/972,896, filed Feb. 11, 2020, U.S.Provisional Application No. 62/972,310, filed Feb. 10, 2020, U.S.Provisional Application No. 62/960,384, filed Jan. 13, 2020, U.S.Provisional Application No. 62/925,258, filed Oct. 24, 2019, U.S.Provisional 62/871,286, filed Jul. 8, 2019, U.S. Provisional 62/871,283,filed Jul. 8, 2019, U.S. Provisional 62/807,356, filed Feb. 19, 2019,and U.S. Provisional 62/807,368, filed Feb. 19, 2019, the contents ofwhich are incorporated in their entirety as if fully set forth herein.

TECHNICAL FIELD

This application relates to methods for the therapeutic treatment ofsymptoms and considerations associated with skin conditions andafflictions, such as rosacea, including moderate to severe rosacea,including topically applying to the skin of a subject in need of saidtreatment a pharmaceutical composition comprising benzoyl peroxide.

BACKGROUND

Rosacea is a chronic disease of inflammatory dermatitis that mainlyaffects the median part of the face and the eyelids of certain adults.It is characterized by telangiectatic erythema, dryness of the skin,papules and pustules. Conventionally, rosacea develops in adults fromthe ages of 30 to 50, and more frequently affects women, although thecondition is generally more severe in men. Rosacea is a primitivelyvascular condition whose inflammatory stage lacks the cysts andcomedones characteristic of common acne.

Factors that have been described as possibly contributing towards thedevelopment of rosacea include, for example: the presence of parasitessuch as the Demodex folliculorum; the presence of bacteria such asHelicobacter pylori (a bacterium associated with gastrointestinaldisorders); hormonal factors (such as endocrine factors); climatic andimmunological factors; and so forth.

Rosacea develops in four stages over several years, in spasms aggravatedby variations in temperature, alcohol, spices, exposure to sunlight andstress. The various stages of the disease are:

Stage 1 (stage of erythema episodes): the patients have erythrosisspasms due to the sudden dilation of the arterioles of the face, whichthen take on a congestive, red appearance. These spasms are caused byemotions, meals and temperature changes.

Stage 2 (stage of couperosis, i.e., of permanent erythema withtelangiectasia): certain patients also have oedema on the cheeks and theforehead.

Stage 3 (inflammatory stage, papulopustular rosacea): patients exhibitappearance of inflammatory papules and pustules, but without affectingthe sebaceous follicles, and thus, does not include cysts and comedones.

Stage 4 (rhinophyma stage): this late phase essentially affects men. Thepatients have a bumpy, voluminous red nose with sebaceous hyperplasiaand fibrous reordering of the connective tissue.

Erythema is a symptom of rosacea, and includes an abnormal and/orsuperficial reddening and inflammation of the skin, usually localized orpatchy, caused by the congestion and dilation of blood capillaries.

Typical treatment of rosacea includes oral or topical administration ofantibiotics such as tetracyclines, salicylic acid, anti-fungal agents,steroids, metronidazole (an anti-bacterial agent) and isotretinoin, ortreatment with anti-infectious agents such as azelaic acid.

SUMMARY

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of moderate to severe erythema symptoms in rosaceapatients, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 12 weeks, to achieve a percentage decrease of about 60% in apopulation exhibiting moderate to severe erythema symptoms when measuredat about 12 weeks after initial treatment of the population with thepharmaceutical composition.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of moderate to severe erythema symptoms in rosaceapatients, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, and whereinafter about 2 weeks of treatment with the pharmaceutical compositionthere is no increase in erythema symptoms.

In other exemplary embodiments, the number of patients with no erythemasymptoms does not increase after treatment for about 2 weeks with thepharmaceutical composition.

In other exemplary embodiments, the percentage decrease in thepopulation exhibiting erythema symptoms after treatment withpharmaceutical composition is at least about 10% to about 30% higherthan a corresponding decrease in the population exhibiting erythemasymptoms after treatment with a vehicle alone.

In other exemplary embodiments, the percentage decrease in thepopulation exhibiting erythema symptoms after treatment withpharmaceutical composition is at least about 18% higher than acorresponding decrease in the population exhibiting erythema symptomsafter treatment with a vehicle alone.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w of the benzoyl peroxide.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 5% w/w of the benzoyl peroxide.

In other exemplary embodiments, the benzoyl peroxide is in a solid,solution or suspension form.

In other exemplary embodiments, the regimen is a first line therapy forthe treatment of moderate to severe rosacea.

In other exemplary embodiments, the moderate to severe rosacea is any oferythematotelengietatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.

In other exemplary embodiments, the pharmaceutical composition is acream or an emulsion.

In other exemplary embodiments, the pharmaceutical composition is anextended-release formulation.

In other exemplary embodiments, an extended-release effect from theextended-release formulation is obtained by encapsulation,microencapsulation, microspheres or coating.

In other exemplary embodiments, the benzoyl peroxide is encapsulated ormicroencapsulated.

In other exemplary embodiments, the benzoyl peroxide is included in amicrosphere or a coating.

Details of other exemplary embodiments of the present disclosure will beincluded in the following detailed description and the accompanyingdrawings. It is appreciated that certain features of the exemplaryembodiments described in this application, which are, for clarity,described in the context of separate embodiments, can also be providedin combination in a single embodiment.

BRIEF DESCRIPTION OF THE DRAWINGS

In order to understand the disclosure and to see how it can be carriedout in practice, embodiments will now be described, by way ofnon-limiting examples only, with reference to the accompanying drawings,in which:

FIGS. 1A and 1B are graphs presenting the percentage of patients witherythema at baseline and after treatment with a BPO composition for aperiod of about 12 weeks compared with the percentage of patients witherythema after treatment with vehicle alone.

DETAILED DESCRIPTION

Multiple studies have been directed to the treatment of rosacea using apharmaceutical or dermatological active agent such as metronidazole,azelaic acid, sulfacetamide, brimonidine, ivermectin, permethrin andclindamycin, and with doxycycline, which is identified as the onlyFDA-approved treatment for rosacea (Oge et al., “Rosacea: Diagnosis andTreatment,” American Family Physician, v. 92(3), pp. 187-198 (2015); Gulet al., “A case of granulomatous rosacea successfully treated withpimecrolimus cream,” J. Derm. Treatment, 19, 313-315 (2008)).

Benzoyl peroxide (BPO) is generally identified as an anti-acne agent,used alone (U.S. Pat. No. 9,439,857; Wester et al., “Controlled releaseof benzoyl peroxide from a porous microsphere polymeric system canreduce topical irritancy,” J. Am. Acad. Derma. 24, 720-726 (1991);Sawleshwarkar, “Multicenter study to evaluate efficacy and irritationpotential of benzoyl peroxide 4% cream in hydrophase base (Brevoxyl) inacne vulgaris,” Ind. J. Derm. Vener. Lepro., 69(1), 19-22 (2003)) or incombination with a primary active such as avermectin (U.S.2011/0052515).

One such study includes a therapeutic regimen involving treatment ofacne rosacea in a group of patients in need of such treatment with 5%BPO-acetone gel for four weeks, followed by treatment of the same groupof patients with 10% BPO-acetone gel for an additional four weeks.(Montes et al., “Topical Treatment of Acne Rosacea with Benzoyl PeroxideAcetone Gel,” Therapeutics for the Clinician: New Reports on TreatmentModalities of Possible Interest to Patient-Caring Physicians, 32,185-190 (1983)). The Montes study showed a significantly better responseduring the five to eight weeks of treatment with 10% BPO-acetone gelcompared to the first four weeks of treatment with 5% BPO-acetone gel.Moreover, although Montes 1983 claims success in the treatment ofrosacea using a BPO-acetone gel, 25% of the patients in the study showedno improvement and 40% of the patients developed an irritation.Additionally, this study required increasing the amount of BPOadministered to the patients from 5% to 10% after week four. The resultsof the Montes 1983 study make it clear that BPO would not be suitablefor regular use in the treatment of rosacea, especially as a first linetreatment of rosacea.

Other studies show that, when used in the treatment of rosacea, BPO isgenerally combined with a primary active agent such as clindamycin(Breneman et al., “Double-blind, randomized, vehicle-controlled clinicaltrial of once-daily benzoyl peroxide/clindamycin topical gel in thetreatment of patients with severe rosacea,” Int. J. Derm., 43, 381-387(2004); Gold et al., “Use of Benzoyl Peroxide/Clindamycin gel in theonce daily treatment of moderate rosacea,” J. Amer. Acad. Dermat.,52(3), sup., P25 (2004); Leyden et al., “Blind photographic review for adouble blind, multicenter, placebo-controlled study comparing BenzoylPeroxide/Clindamycin and placebo for the treatment of rosacea,” J. Amer.Acad. Dermat., 52(3), sup., P14 (2004); Goldgar et al., “TreatmentOptions for Acne Rosacea,” J Amer. Fam. Physician, 80(5), 461-468(2009)).

BPO is generally identified as only a possible second-line treatment ofrosacea following the use of another, different active. (Oge 2015, Table5; Goldgar 2009, “Key Recommendations for Practice”). Goldgar 2009, inparticular, recommends the use of BPO only as a tertiary therapy for thetreatment of rosacea.

When BPO was used as the sole active agent for the treatment of rosacea,lesions were found to be unresponsive. (Gul 2008).

These previous rosacea treatments with BPO alone or in combination withother agents, have been shown to have several drawbacks such asirritation and intolerance phenomena, especially when they areadministered for a prolonged period. (Crawford et al., “Rosacea: I.Etiology, pathogenesis, and subtype classification,” J. Am. Acad.Dermatol., 51, 327-341 (2004)). These treatments are only suppressiveand not curative, acting especially on the pustulous spasms occurringduring the inflammatory stage.

Such drawbacks associated with the treatment of rosacea involving theuse of BPO result in exclusion of BPO from standard rosacea treatmentmethods. For example, A Review of the Current Modalities for theTreatment of Papulopustular Rosacea identifies metronidazole, ivermectinand azelaic acid as topical therapies that were proven effective for thetreatment of rosacea. (McGregor et al., “A Review of the CurrentModalities of the Treatment of Papulopustular Rosacea,” Dermatol. Clin.(2017)). While McGregor 2017 mentions alternate therapies, such assodium sulfacetanide/sulfur cream, clindamycin, tretinoin, calcineurininhibitors and oral tretinoin, that may have some effectiveness in thetreatment of rosacea, notably, McGregor 2017 does not include BPO in thelong list of possible treatment therapies described therein. The absenceof BPO as a known treatment for rosacea is also evident in otherstudies. (Feaster et al., “Clinical effectiveness of novel rosaceatherapies,” Current Op. Pharmacol., 46, 14-18 (2019); Del Rosso et al.,“Update on the Management of Rosacea from the American Acne & RosaceaSociety (AARS); J. Clinical & Aesthetic Dermat., 12 (6), 17-24 (2019)).The absence of BPO as a recognized first-line treatment for rosacea isespecially evident in Del Rosso, which is a well-known and respectedauthority on the treatment of rosacea. The AARS review lists theSociety's recommendation for rosacea treatment, including topicalmetronidazole, topical azelaic acid, oral tetracyclines, ivermectin,topical alpha agonists, and oral isotretinoin, as well as “alternativetherapies,” such as sulfacetamide/sulfur, calcineurin inhibitors,retinoids, and permethrin. (See e.g., Table 1 of the AARS review.) BPOis not mentioned in the AARS review either as a leading or analternative therapeutic agent for the treatment of rosacea.

Considering the chronic nature of rosacea, there is a need for earlyonset of action, and a prolonged use and/or treatment of the disease,its symptoms and associated conditions, in a safe and effective manner.Thus, there exists a need for compositions that show early onset ofaction, and improved efficacy in the treatment of rosacea, that impartgreater tolerance to the active principles and that reduce,substantially minimize or do not have the side effects described in theprior art.

Advantages and features of the present disclosure, and methods foraccomplishing the same will be more clearly understood from exemplaryembodiments described below with reference to any accompanying drawingsand figures. However, the present disclosure is not limited to thefollowing exemplary embodiments and can be implemented in variousdifferent forms. The exemplary embodiments are provided only to providesufficient disclosure of the present discoveries and to fully provide aperson having ordinary skill in the art to which the present disclosurepertains within the technical field, and the present disclosure will bedefined by any appended claims and combinations thereof.

As used herein, like reference numerals generally denote like elementsthroughout the present specification. Further, in the followingdescription, a detailed explanation of well-known related technologiescan be omitted to avoid unnecessarily obscuring the subject matter ofthe present disclosure.

As used herein, terms such as “including” and “having” are generallyintended to allow other components to be included unless the terms areused in conjunction with the term “only.”

As used herein, the term “topical use” is meant to encompass the topicaladministration of an exemplary composition by formulating saidcomposition in any way known in the art, or in formulations disclosedherein, which are compatible with the skin, mucous membranes and/or theinteguments.

As used herein, the term “treating” or “treatment” includes curing acondition, treating a condition, preventing or substantially preventinga condition, treating symptoms of a condition, curing symptoms of acondition, ameliorating, reducing and/or minimizing symptoms of acondition, treating effects of a condition, ameliorating, reducingand/or minimizing effects of a condition, and preventing and/orsubstantially preventing results of a condition.

As used herein, the term “first-line therapy” or “first-line treatment”means a therapy or treatment for which its label does not include arequirement or recommendation that said therapy or treatment should beused only after other therapies or treatments were shown to beunsatisfactory or unsuccessful. It can also include a therapy and/ortreatment wherein no other actives (beyond the main active) areadministered to the individual subject in need.

As used herein, the term “success rate” corresponds to a percentageincrease in the number of subjects achieving clear or almost clear skinon the investor global assessment (IGA) scale after treatment with thepharmaceutical composition.

As used herein, the term “early onset” or “early onset of action” meansachieving a desired result and/or effect at a point in time that isearlier or even much early than achieved using a vehicle or other,conventional treatment approach. For example, it can mean achieving adesired result and/or effect no later than about 8 weeks from initialtreatment, preferably no later than about 4 weeks from initialtreatment, and more preferably no later than about 2 weeks from initialtreatment.

As used herein, the term “pharmaceutical composition” refers to acomposition comprising one or more active ingredients with othercomponents such as, for example, pharmaceutically acceptable ingredientsand/or excipients. The purpose of a pharmaceutical composition is tofacilitate administration of an active ingredient to a subject.

As used herein, the terms “pharmaceutically active agent” or “activeagent” or “active pharmaceutical ingredient” are interchangeable andmean the ingredient is a pharmaceutical drug, which is biologically-and/or chemically-active and is regulatory-approved or approvable assuch.

As used herein, the term “ingredient” refers to a pharmaceuticallyacceptable ingredient, which is included or is amenable to be includedin The FDA's Inactive Ingredient (IIG) database. Inactive ingredientscan sometimes exhibit some therapeutic effects, although they are notdrugs.

As used herein, the term “adverse events values” refers to an averagepercentage of subjects that experience any adverse events associatedwith the treatment of rosacea with a composition described and/orclaimed herein (usually on a surface of the skin of a subject treatedwith a composition described and/or claimed herein). A non-limiting listof such adverse events includes: irritation, dryness, scaling, itchingpurities, burning, stinging, combinations thereof and the like.

As used herein, the term “inflammatory lesion” refers to papules andpustules present on the skin of a patient, and does not include nodulesand cysts.

As used herein, the term “papule” refers to a solid, elevatedinflammatory lesion equal to or less than about 5 mm in diameter.

As used herein, the term “pustule” refers to an elevated inflammatory,pus-containing lesion equal to or less than about 5 mm in diameter.

As used herein, the term “nodule” and/or “cyst” refers to palpable solidinflammatory lesion, greater than about 5 mm in diameter. The noduleand/or cyst may have depth but does not necessarily include elevation.

Whenever a numerical range is indicated herewith, it is meant to includeany cited numeral (fractional or integral) within the indicated range.The phrases “ranging/ranges between” a first indicated number and asecond indicated number and “ranging/ranges from” a first indicatednumber “to” a second indicated number are used herein interchangeableand are meant to include the first and second indicated numbers and allfractional and integral numerals therebetween.

The dimensions and values disclosed herein are not to be understood asbeing strictly limited to the exact numerical values recited. Instead,unless otherwise specified, each such dimension is intended to mean boththe recited value and a functionally equivalent range surrounding thatvalue. For example, a dimension disclosed as “10 μm” is intended to mean“about 10 μm.”

As used herein, numbers and/or numerical ranges preceded by the term“about” should not be considered to be limited to the recited range.Rather, numbers and/or numerical ranges preceded by the term “about”should be understood to include a range accepted by those skilled in theart for any given element in formations according to the subjectinvention.

As used herein, when a numerical value is preceded by the term “about,”the term “about” is intended to indicate +/−10%.

As used herein, the singular form “a,” “an” and “the” include pluralreferences unless the context clearly dictates otherwise. For example,the term “a compound” or “at least one compound” can include a pluralityof compounds, including combinations and/or mixtures thereof.

As used herein, the term “method” refers to manners, means, techniquesand procedures for accomplishing a given task including, but not limitedto, those manners, means, technical and procedures either known to, orreadily developed from known manners, means, techniques and proceduresby practitioners of the chemical, pharmacological, biological,biochemical and medical arts.

It is appreciated that certain features of the exemplary embodimentsdescribed herein, which are, for clarity, described in the context ofseparate embodiments, can also be provided in combination in a singleembodiment. Conversely, various features of the exemplary embodiments,which are, for brevity, described in the context of a single embodiment,can also be provided separately or in any suitable sub-combination or assuitable in any other described embodiment. Certain features describedin the context of various embodiments are not to be considered essentialfeatures of those embodiments, unless the embodiment is inoperativewithout those elements.

An exemplary embodiment of this application is a regimen for thetherapeutic treatment of moderate to severe erythema symptoms in rosaceapatients, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, wherein saidpharmaceutical composition is applied once daily for a period of atleast about 12 weeks, to achieve a percentage decrease of about 60% in apopulation exhibiting moderate to severe erythema symptoms when measuredat about 12 weeks after initial treatment of the population with thepharmaceutical composition.

In another exemplary embodiment, the percentage decrease in thepopulation exhibiting erythema symptoms after treatment withpharmaceutical composition is at least about 10% to about 30% higherthan a corresponding decrease in the population exhibiting erythemasymptoms after treatment with a vehicle alone.

In another exemplary embodiment, the percentage decrease in thepopulation exhibiting erythema symptoms after treatment withpharmaceutical composition is at least about 18% higher than acorresponding decrease in the population exhibiting erythema symptomsafter treatment with a vehicle alone.

Another exemplary embodiment of this application is a regimen for thetherapeutic treatment of moderate to severe erythema symptoms in rosaceapatients, the regimen comprising topically applying to the skin of asubject in need of said treatment a pharmaceutical composition, thepharmaceutical composition comprising about 1% w/w to about 10% w/wbenzoyl peroxide as an active ingredient, and a pharmaceuticallyacceptable carrier or excipient, wherein the benzoyl peroxide is theonly active ingredient in said pharmaceutical composition, and whereinafter about 2 weeks of treatment with the pharmaceutical compositionthere is no increase in erythema symptoms.

In other exemplary embodiments, the benzoyl peroxide is the sole activeingredient administered to the subject during the duration of theregimen.

In other exemplary embodiments, the pharmaceutical composition comprisesabout 2.5% w/w to about 10% w/w of benzoyl peroxide, preferably about 3%to about 9%, about 4% to about 8%, and more preferably about 5% w/w ofbenzoyl peroxide.

In other exemplary embodiments, the benzoyl peroxide is selected fromsolid, solution or suspension form.

In other exemplary embodiments, the regimen is a first line therapy forthe treatment of rosacea.

In other exemplary embodiments, the rosacea is any one oferythematotelengietatic rosacea, papulopustular rosacea, phymatousrosacea or ocular rosacea.

In other exemplary embodiments, the rosacea is moderate to severerosacea, preferably severe rosacea.

In other exemplary embodiments, the pharmaceutical composition is acream or an emulsion.

In other exemplary embodiments, the pharmaceutical composition is anextended release formulation. The extended-release effect can beobtained by encapsulation, microencapsulation, microspheres or coating.The benzoyl peroxide can be encapsulated or microencapsulated, thebenzoyl peroxide can be included in a microsphere or a coating, and thelike.

In some further embodiments, the composition further comprises at leastone non pharmaceutical active additive selected from the groupconsisting of chelating agents, antioxidants, sunscreens, preservatives,fillers, electrolytes, humectants, dyes, mineral or organic acids orbases, fragrances, essential oils, moisturizers, vitamins, essentialfatty acids, sphingolipids, self-tanning compounds, calmatives andskin-protecting agents, pro-penetrating agents and gelling agents, or amixture and/or combination thereof.

In other embodiments, the composition is formulated into a topicallyapplicable, physiologically acceptable medium comprising of: (a) atleast one member selected from the group consisting of water, alcohols,oils, fatty substances and waxes; and (b) at least one additive selectedfrom the group consisting of chelating agents, antioxidants, sunscreens,preservatives, fillers, electrolytes, humectants, dyes, mineral acids,mineral bases, organic acids, organic bases, fragrances, essential oils,moisturizers, vitamins, essential fatty acids, sphingolipids,self-tanning compounds, calmatives, skin-protecting agents,pro-penetrating agents, gelling agents, emulsifiers, co-emulsifiers, andmixtures and/or combinations thereof.

In some embodiments the composition is formulated as an emulsion(including an oil-in-water emulsion, a water-in-oil emulsion, multipleemulsions and microemulsions). In other embodiments, the composition isformulated as a cream.

The compositions described in exemplary embodiments herein arepharmaceutical compositions, and especially dermatological compositions,which can be in any galenical form conventionally used for topicalapplication. By addition of a fatty or oily phase, they can also be inthe form of dispersions of the lotion or serum type, emulsions of liquidor semi-liquid consistency of the milk type obtained by dispersing afatty phase in an aqueous phase (O/W) or conversely (W/O), orsuspensions or emulsions of soft, semiliquid or solid consistency of thecream, gel or ointment type, or alternatively multiple emulsions (W/O/Wor O/W/O), microemulsions, microcapsules, microparticles and/orvesicular dispersions of ionic and/or nonionic type, and/or wax/aqueousphase dispersions. These compositions are formulated according to theusual methods.

In further embodiments, the composition comprises, as a singlepharmaceutical active agent, benzoyl peroxide in a solid form, fortopical use in the treatment of rosacea, is an oil in water emulsioncomprising a polyoxylstearate and a glycerylstearate. Various methodsfor the preparation of the BPO-containing compositions are described inU.S. Application Publication Nos. 2010/0016443, 2017/0281571 and2018/0147165 and U.S. Pat. No. 9,687,465.

In some embodiments, the ratio of said polyoxylstearate to saidglycerylstearate is in the range of about 0.1:10 to about 10:0.1.

In yet further embodiments, said polyoxylstearate is selected from thegroup consisting of Polyoxyl-8 stearate, Polyoxyl-20 stearate,Polyoxyl-40 stearate, Polyoxyl-100 stearate and combinations and/ormixtures thereof.

In further embodiments, said glycerylstearate is selected from the groupconsisting of glyceryl mono-stearate, glyceryl di-stearate andcombinations and/or mixtures thereof.

In other embodiments, said polyoxylstearate in said composition is inthe range of from about 0.1% w/w to about 30% w/w.

In further embodiments, the amount of said glycerylstearate in saidcomposition is in the range of from about 0.1% w/w to about 30% w/w.

In other embodiments, said composition further comprises at least onefatty alcohol.

In other embodiments, said at least one fatty alcohol is selected fromthe group consisting of octyl alcohol, 2-ethyl hexanol. nonyl alcohol,decyl alcohol, undecanol, dodecyl alcohol, tridecyl alcohol, tetradecylalcohol, pentadecyl alcohol, cetyl alcohol, palmitoleyl alcohol,heptadecyl alcohol, cetostearyl alcohol, stearyl alcohol, isostearylalcohol, elaidyl alcohol, oleyl alcohol, linoleyl alcohol,elaidolinolenyl alcohol, ricinoleyl alcohol, nonadecyl alcohol,arachidyl alcohol, heneicosyl alcohol. behenyl alcohol, erucyl alcohol,lignoceryl alcohol, ceryl alcohol, montanyl alcohol, cluytyl alcohol,myricyl alcohol, melissyl alcohol, geddyl alcohol, cetearyl alcohol andcombinations and/or mixtures thereof.

In further embodiments, the amount of said at least one fatty alcohol insaid composition is in the range of from about 0.2% w/w to about 50%w/w.

In yet other embodiments, said composition further comprises apolyacrylic acid homopolymer or copolymer.

In other embodiments, said oil in said oil in water emulsion is selectedfrom the group consisting of paraffin oil, isopropyl myristate,caprylic/capric triglyceride, squalane, squalene, almond oil, castoroil, olive oil, jojoba oil, sunflower oil, soybean oil, grape seed oil,dimethicone, cyclomethicone and combinations and/or mixtures thereof.

In further embodiments, said oil in present in the composition in anamount in the range of from about 0.05% w/w to about 50% w/w.

In some embodiments, said water in said oil in water emulsion furthercomprises at least one water soluble humectant.

In other embodiments, said at least one water soluble humectant isselected from the group consisting of propylene glycol, glycerin,polyethylene glycol-X and combinations and/or mixtures thereof, where Xis in the range of from about 200 to about 10,000.

In some embodiments, the composition comprises said solid BPO in acontrolled and/or slowed release drug delivery system. In furtherembodiments, said controlled and/or slowed release drug delivery systemis an encapsulation in a microcapsule, wherein said solid BPO isembedded in said microcapsule. When referring to a “controlled and/orslowed release drug delivery system” it should be understood to relateto a delivery system (which in the present application is a topicaldelivery system) that enables the release of the pharmaceutical activeagent in predetermined amounts over a specified period. In someembodiments, said system is a core-shell system of a microcapsule and/ora porous matrix structure, such as, for example, a microsponge. The term“embedded” should be understood to encompass an inert system thatprovides a barrier between the pharmaceutical active agent, i.e. BPO,and its surrounding environment in the composition. In some embodiments,said agent is entrapped and/or encapsulated in said controlled releasesystem.

In some embodiments, said core of said microcapsule comprises orconsists of said solid BPO.

In some further embodiments, said microcapsules are a core shellmicrocapsule. The shell comprises at least one inorganic polymer. Insome other embodiments, said inorganic polymer of said shell is a metaloxide or semi-metal oxide shell (layer).

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising orconsisting of solid BPO.

In some embodiments, said microcapsule comprises a metal oxide orsemi-metal oxide coating or layer (shell) and a core comprising solidBPO is prepared by a process comprising the steps of:

(a) contacting a solid BPO particulate matter with an ionic additive andan aqueous medium to obtain a dispersion of said particulate matterhaving positive charges on its surface;

(b) subjecting the particulate matter to a coating procedure comprisingprecipitating a metal oxide salt onto the surface of the particulatematter to form a metal oxide layer thereon thereby to obtain particulatematter coated by a metal oxide coating layer;

(c) repeating step (b) at least 4 more times: and

(d) aging said coating layer.

As used herein, the term “solid BPO particulate matter” refers to asolid BPO having solubility in water of less than about 1% w/w,typically less than about 0.5% and at times less than about 0.1% w/w atroom temperature (about 20° C.). The “solid BPO particulate matter”constitutes the “core” of the particles obtained by the process. Thesolid BPO particulate matter, is, in some embodiments, in such a stateof subdivision that it can be suspended in water, e.g., in the form of afinely-divided powder having a D₉₀ (see definition below), in someembodiments in the range of from about 0.3 to about 50 microns. Such aparticulate matter can be readily suspended in an aqueous systems bystirring, with or without the aid of a surfactant.

The terms “solid BPO particulate matter” and “particulate matter” willbe used interchangeably.

In the present application, the terms “layer”, “coating” or “shell” andsimilar terms, refer to a layer of metal oxide or semi-metal oxideformed around a particle or particulate matter. The layer or coatingneed not always be complete or uniform and need not necessarily lead tocomplete coverage of the particulate matter or particle surface. It isappreciated that upon repetition of the coating steps as the coatingprocess proceeds a more uniform coating and more complete coverage ofthe particulate matter is obtained.

The term “dispersion,” as used herein, in step (a) of the process refersto a solid dispersion of the particulate matter in the aqueous medium.Step (a) of the process can further comprise reducing the particle sizeof the particulate matter to the desired particle size, for example, bymilling or homogenization.

The core (i.e., solid, BPO particulate matter) can be of any shape, forexample, rod-like, plate-like, ellipsoidal, cubic, spherical shape,combinations thereof and the like.

Reference to the size of particles will be made through their D₉₀, whichmeans that about 90% of the particles have the stated dimension or less(measured by volume). Thus, for example, for spherical particles statedto have a diameter of about 10 micrometer (“microns”), this means thatthe particles have a D₉₀ of about 10 microns. The D₉₀ can be measured bylaser diffraction. For particles having a shape other than spheres, theD₉₀ refers to the mean average of the diameter of a plurality ofparticles.

In the case of cores having a spherical shape, the D₉₀ can be in therange of from about 0.3 to 90 microns, in some embodiments from about0.3 to about 50 microns, in some other embodiments from about 1 to about50 microns, in some further embodiments from about 5 to about 30microns. As used herein, the phrase “D₉₀ can be in the range of fromabout 0.3 microns to about 90 microns” means about 90% by volume of theparticles (in this case the particle's core) can be less than or equalto a value in the range of from about 0.3 microns to about 90 microns.

For generally cubic-shaped cores or cores having a shape resembling thatof a cube, the mean size of a side can be in the range of from about 0.3to about 80 microns, in some embodiments from about 0.3 to about 40microns, in some further embodiments from about 0.8 to about 40 microns,in some further embodiments from about 4 to about 15 microns.

For rod-like shaped, ellipsoidal-shaped and plate-like shaped cores, thelargest dimension (that of the longest axis) is typically in the rangeof from about 10 to about 100 microns, in some embodiments from about 15to about 50 microns; and the smallest dimension is typically in therange of from about 0.5 to about 20 microns, in some further embodimentsfrom about 2 to about 10 microns.

As used herein, unless otherwise indicated, the term “particle” refersto the metal oxide or semi-metal oxide coated particulate matter.

It is appreciated that some of the particles obtained by the process canat times be formed from two or more original particles of the solid BPOparticulate and can accordingly include at times more than one core,such cores being separated from each other by a metal oxide region.

The weight of the solid BPO particulate (core material) based on thetotal weight of the particle can be in the range of from about 99% w/wto about 50% w/w, in some embodiments in the range of from about 97% w/wto about 50% w/w. The core material can be in a crystalline form,amorphous form, or combination thereof. The core material can be acosmetic, pharmaceutical or an agrochemical active ingredient.

Exemplary Embodiments

BPO-containing compositions were prepared following the variouspreparation methods described in U.S. Application Publication Nos.2010/0016443, 2017/0281571 and 2018/0147165 and U.S. Pat. No. 9,687,465,the contents of which are incorporated herein, by reference, in theirentirety.

Description:

A randomized, double-blind, multi-center, parallel group, active- andvehicle-controlled study of encapsulated 5% benzoyl peroxide cream(E-BPO) and vehicle cream was performed to assess the efficacy andsafety of E-BPO compared to vehicle. Study duration was 12 weeks andincluded approximately 350 male and female patients afflicted withpapulopustular rosacea. Patients were at least 18 years of age.

Patients were admitted into the study after meeting allinclusion/exclusion criteria, including a clinical diagnosis of rosacea.Subjects with moderate to severe rosacea who were appropriate forsystemic treatment were counseled regarding their treatment options bythe Principal Investigator. At each visit, a 5-point IGA scale ofrosacea and inflammatory lesion counts were performed and recorded.

Dosing:

Patients were randomly organized in a 2:1 ratio to the study product orvehicle treatment group, respectively. Patients applied the studyproduct once daily for 12 weeks on the face in a thin layer to provideeven distribution.

Clinical and Safety Evaluations were performed at Baseline and Weeks 2,4, 8 and 12.

Evaluation of Erythema:

Erythema is defined as redness of the skin. Erythema was scored on ascale of 0 (none) to 3 (severe) at all visits.

The percentage of patients with no erythema at baseline with 5% E-BPOand vehicle cream at Baseline and about 2 weeks is shown in Tables 1Aand 1B below. As seen from these results, the percentage of patientswith no erythema symptoms does not increase after treatment with 5%E-BPO for two weeks.

TABLE 1A Comparative Example 1A Example 1A (5% E-BPO) (vehicle alone)Baseline Percentage of 0.4 0.0 (N = 243 for 5% Patients with E-BPO; N =118 for No Erythema vehicle) Symptoms Week 2 Percentage of 0.4 0.0 (N =221 for 5% Patients with E-BPO; N = 107 for No Erythema vehicle)Symptoms Change from 0.0 0.0 baseline Percentage 0.0 0.0 change frombaseline

TABLE 1B Comparative Example 1B Example 1B (5% E-BPO) (vehicle alone)Baseline Percentage of 0.4 0.0 (N = 243 for 5% Patients with E-BPO; N =118 for No Erythema vehicle) Symptoms Week 2 Percentage of 1.2 0.0 (N =221 for 5% Patients with E-BPO; N = 107 for No Erythema vehicle)Symptoms Change from 0.8 0.0 baseline Percentage 20 0.0 change frombaseline

The Rosacea Erythema Assessment Scale for patient groups treated with 5%E-BPO and vehicle cream at Baseline and about 12 weeks is shown inTables 2A and 2B below. As seen from these results, a percentagedecrease of about 60% is observed in a population exhibiting moderate tosevere erythema symptoms when measured at about 12 weeks after initialtreatment of the population with the pharmaceutical composition. Thisobserved decrease in erythema symptoms is at least about 10% to about30% higher than a corresponding decrease in the population exhibitingerythema symptoms after treatment with a vehicle alone. These resultsare shown in FIGS. 1A and 1B.

TABLE 2A Comparative Example 1A Example 1A (5% E-BPO) (vehicle alone)Baseline Percentage of 85.6 87.2 (N = 243 for 5% Patients with E-BPO; N= 118 for Moderate and vehicle) Severe Erythema Week 12 Percentage of33.0 57.9 (N = 221 for 5% Patients with E-BPO; N = 107 for Moderate andvehicle) Severe Erythema Change from −52.6 −29.3 baseline Percentage−61.4 −33.6 change from baseline

TABLE 2B Comparative Example 1B Example 1B (5% E-BPO) (vehicle alone)Baseline Percentage of 94.0 95.9 (N = 250 for 5% Patients with E-BPO; N= 122 for Moderate and vehicle) Severe Erythema Week 12 Percentage of38.7 48.7 (N = 235 for 5% Patients with E-BPO; N = 113 for Moderate andvehicle) Severe Erythema Change from −55.3 −47.2 baseline Percentage−58.8 −49.2 change from baseline

The above-discussed results demonstrate the unexpected superiority ofthe benzoyl peroxide composition described in this application in thetreatment of severe rosacea in patients in need of such treatment.

Although the exemplary embodiments of the present disclosure have beendescribed in detail with reference to the accompanying examples anddrawings, the present disclosure is not limited thereto and can beembodied in many different forms without departing from the technicalconcept of the present disclosure. Therefore, the exemplary embodimentsof the present disclosure are provided for illustrative purposes onlyand are not intended to limit the technical concept of the presentdisclosure. The protective scope of the present disclosure should beconstrued based on any appended claims and combinations thereof, and allthe technical concepts in the equivalent scope thereof should beconstrued as falling within the scope of the present disclosure. Asvarious changes could be made in the above methods and compositionswithout departing from the scope of the invention, it is intended thatall matter contained in the above description shall be interpreted asillustrative and not in a limiting sense. Other embodiments within thescope of the claims herein will be apparent to one skilled in the artfrom consideration of the specification or practice of the exemplaryembodiments disclosed herein. It is intended that the specification beconsidered exemplary only, with the scope and spirit of the describedsubject matter being indicated by the claims.

What is claimed is:
 1. A regimen for the therapeutic treatment ofmoderate to severe erythema symptoms in rosacea patients, the regimencomprising topically applying to the skin of a subject in need of saidtreatment a pharmaceutical composition, the pharmaceutical compositioncomprising about 2.5% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, wherein said pharmaceutical composition isapplied once daily for a period of at least about 12 weeks, to achieve apercentage decrease of about 60% in a population exhibiting moderate tosevere erythema symptoms when measured at about 12 weeks after initialtreatment of the population with the pharmaceutical composition, andwherein the percentage decrease in the population exhibiting erythemasymptoms after treatment with pharmaceutical composition is at leastabout 10% to about 30% higher than a corresponding decrease in thepopulation exhibiting erythema symptoms after treatment with a vehiclealone.
 2. The regimen of claim 1, wherein the percentage decrease in thepopulation exhibiting erythema symptoms after treatment withpharmaceutical composition is at least about 18% higher than acorresponding decrease in the population exhibiting erythema symptomsafter treatment with a vehicle alone.
 3. The regimen of claim 1, whereinthe benzoyl peroxide is the sole active ingredient administered to thesubject during the duration of the regimen.
 4. The regimen of claim 1,wherein the pharmaceutical composition comprises about 5% w/w of thebenzoyl peroxide.
 5. The regimen of claim 1, wherein the benzoylperoxide is in a solid, solution or suspension form.
 6. The regimen ofclaim 1, wherein the regimen is a first line therapy for the treatmentof moderate to severe rosacea.
 7. The regimen of claim 1, wherein themoderate to severe rosacea is any of erythematotelengietatic rosacea,papulopustular rosacea, phymatous rosacea or ocular rosacea.
 8. Theregimen of claim 1, wherein said pharmaceutical composition is a creamor an emulsion.
 9. The regimen of claim 1, wherein said pharmaceuticalcomposition is an extended-release formulation.
 10. The regimen of claim9, wherein an extended-release effect from the extended-releaseformulation is obtained by encapsulation, microencapsulation,microspheres or coating.
 11. The regimen of claim 10, wherein thebenzoyl peroxide is encapsulated or microencapsulated.
 12. The regimenof claim 10, wherein the benzoyl peroxide is included in a microsphereor a coating.
 13. A regimen for the therapeutic treatment of moderate tosevere erythema symptoms in rosacea patients, the regimen comprisingtopically applying to the skin of a subject in need of said treatment apharmaceutical composition, the pharmaceutical composition comprisingabout 2.5% w/w to about 10% w/w benzoyl peroxide as an activeingredient, and a pharmaceutically acceptable carrier or excipient,wherein the benzoyl peroxide is the only active ingredient in saidpharmaceutical composition, and wherein after about 2 weeks of treatmentwith the pharmaceutical composition there is no increase in erythemasymptoms.
 14. The regimen of claim 13, wherein the number of patientswith no erythema symptoms does not increase after treatment for about 2weeks with the pharmaceutical composition.
 15. The regimen of claim 13,wherein the pharmaceutical composition comprises about 5% w/w of thebenzoyl peroxide.
 16. The regimen of claim 13, wherein the benzoylperoxide is in a solid, solution or suspension form.
 17. The regimen ofclaim 13, wherein the regimen is a first line therapy for the treatmentof moderate to severe rosacea.
 18. The regimen of claim 13, wherein themoderate to severe rosacea is any of erythematotelengietatic rosacea,papulopustular rosacea, phymatous rosacea or ocular rosacea.
 19. Theregimen of claim 13, wherein said pharmaceutical composition is a creamor an emulsion.
 20. The regimen of claim 13, wherein said pharmaceuticalcomposition is an extended-release formulation.
 21. The regimen of claim20, wherein an extended-release effect from the extended-releaseformulation is obtained by encapsulation, microencapsulation,microspheres or coating.
 22. The regimen of claim 21, wherein thebenzoyl peroxide is encapsulated or microencapsulated.
 23. The regimenof claim 21, wherein the benzoyl peroxide is included in a microsphereor a coating.